Singapore's health-care system: key features, challenges, and shifts.

Since Singapore became an independent nation in 1965, the development of its health-care system has been underpinned by an emphasis on personal responsibility for health, and active government intervention to ensure access and affordability through targeted subsidies and to reduce unnecessary costs. Singapore is achieving good health outcomes, with a total health expenditure of 4·47% of gross domestic product in 2016. However, the health-care system is contending with increased stress, as reflected in so-called pain points that have led to public concern, including shortages in acute hospital beds and intermediate and long-term care (ILTC) services, and high out-of-pocket payments. The main drivers of these challenges are the rising prevalence of non-communicable diseases and rapid population ageing, limitations in the delivery and organisation of primary care and ILTC, and financial incentives that might inadvertently impede care integration. To address these challenges, Singapore's Ministry of Health implemented a comprehensive set of reforms in 2012 under its Healthcare 2020 Masterplan. These reforms substantially increased the capacity of public hospital beds and ILTC services in the community, expanded subsidies for primary care and long-term care, and introduced a series of financing health-care reforms to strengthen financial protection and coverage. However, it became clear that these measures alone would not address the underlying drivers of system stress in the long term. Instead, the system requires, and is making, much more fundamental changes to its approach. In 2016, the Ministry of Health encapsulated the required shifts in terms of the so-called Three Beyonds-namely, beyond health care to health, beyond hospital to community, and beyond quality to value.

Temperature-modulated water filtration using microgel-functionalized hollow-fiber membranes.

In the present work, we investigate the potential of aqueous polymer microgels in membrane technology, especially for filtration applications. The poly(N-vinylcaprolactam)-based microgels exhibit thermoresponsive behavior and were employed to coat hollow-fiber membranes used for micro- and ultrafiltration. We discuss the preparation of microgel-modified membranes (by "inside-out" as well as "outside-in" filtration in dead-end mode). The clean-water permeability and stability of these membranes was studied not only as a function of time, but also of temperature. The microgel-modified membranes exhibit a reversible thermoresponsive behavior whereby both the resistance and the retention increased with decreasing temperature.

Magnetically triggered clustering of biotinylated iron oxide nanoparticles in the presence of streptavidinylated enzymes.

This work deals with the production and characterization of water-compatible, iron oxide based nanoparticles covered with functional poly(ethylene glycol) (PEG)-biotin surface groups (SPIO-PEG-biotin). Synthesis of the functionalized colloids occurred by incubating the oleate coated particles used as precursor magnetic fluid with anionic liposomes containing 14 mol% of a phospholipid-PEG-biotin conjugate. The latter was prepared by coupling dimyristoylphosphatidylethanolamine (DC(14:0)PE) to activated α-biotinylamido-ω -N-hydroxy-succinimidcarbonyl-PEG (NHS-PEG-biotin). Physical characterization of the oleate and PEG-biotin iron oxide nanocolloids revealed that they appear as colloidal stable clusters with a hydrodynamic diameter of 160 nm and zeta potentials of - 39 mV (oleate coated particles) and - 14 mV (PEG-biotin covered particles), respectively, as measured by light scattering techniques. Superconducting quantum interference device (SQUID) measurements revealed specific saturation magnetizations of 62-73 emu g(-1) Fe(3)O(4) and no hysteresis was observed at 300 K. MR relaxometry at 3 T revealed very high r(2) relaxivities and moderately high r(1) values. Thus, both nanocolloids can be classified as small, superparamagnetic, negative MR contrast agents. The capacity to functionalize the particles was illustrated by binding streptavidin alkaline phosphatase (SAP). It was found, however, that these complexes become highly aggregated after capturing them on the magnetic filter device during high-gradient magnetophoresis, thereby reducing the accessibility of the SAP.

Polyelectrolyte coating of iron oxide nanoparticles for MRI-based cell tracking.

Iron oxide-based magnetic nanoparticles (MNPs) offer unique properties for cell tracking by magnetic resonance imaging (MRI) in cellular immunotherapy. In this study, we investigated the uptake of chemically engineered NPs into antigen-presenting dendritic cells (DCs). DCs are expected to perceive MNPs as foreign antigens, thus exhibiting the capability to immunologically sense MNP surface chemistry. To systematically evaluate cellular uptake and T2/T2(⁎) MR imaging properties of MNPs, we synthesized polymer-based MNPs by employing layer-by-layer (LbL) technology. Thereby, we achieved modification of particle shell parameters, such as size, surface charge, and chemistry. We found that subcellular packaging of MNPs rather than MNP content in DCs influences MR imaging quality. Increased local intracellular electron density as inferred from transmission electron microscopy (TEM) strongly correlated with enhanced contrast in MRI. Thus, LbL-tailoring of MNP shells using polyelectrolytes that impact on uptake and subcellular localization can be used for modulating MR imaging properties. FROM THE CLINICAL EDITOR: In this study, layer-by-layer tailoring of magnetic NP shells was performed using polyelectrolytes to improve uptake by dendritic cells for cell-specific MR imaging. The authors conclude that polyelectrolyte modified NP-s can be used for modulating improving MR imaging quality by increasing subcellular localization.

Polyelectrolyte Coating of Ferumoxytol Differentially Impacts the Labeling of Inflammatory and Steady-State Dendritic Cell Subtypes.

Engineered magnetic nanoparticles (MNPs) are emerging as advanced tools for medical applications. The coating of MNPs using polyelectrolytes (PEs) is a versatile means to tailor MNP properties and is used to optimize MNP functionality. Dendritic cells (DCs) are critical regulators of adaptive immune responses. Functionally distinct DC subsets exist, either under steady-state or inflammatory conditions, which are explored for the specific treatment of various diseases, such as cancer, autoimmunity, and transplant rejection. Here, the impact of the PE coating of ferumoxytol for uptake into both inflammatory and steady-state DCs and the cellular responses to MNP labeling is addressed. Labeling efficiency by uncoated and PE-coated ferumoxytol is highly variable in different DC subsets, and PE coating significantly improves the labeling of steady-state DCs. Uncoated ferumoxytol results in increased cytotoxicity of steady-state DCs after labeling, which is abolished by the PE coating, while no increased cell death is observed in inflammatory DCs. Furthermore, uncoated and PE-coated ferumoxytol appear immunologically inert in inflammatory DCs, but they induce activation of steady-state DCs. These results show that the PE coating of MNPs can be applied to endow particles with desired properties for enhanced uptake and cell type-specific responses in distinct target DC populations.

Clinical Diagnostic Study of a Novel Injection Molded Swab for SARS-Cov-2 Testing.

INTRODUCTION: The gold standard for COVID-19 diagnosis is currently a real-time reverse transcriptase polymerase chain reaction (RT-PCR) to detect SARS-CoV-2. This is most commonly performed on respiratory secretions obtained via a nasopharyngeal swab. Due to supply chain limitations and high demand worldwide because of the COVID-19 pandemic, access to commercial nasopharyngeal swabs has not been assured. 3D printing methods have been used to meet the shortfall. For longer-term considerations, 3D printing may not compare well with injection molding as a production method due to the challenging scalability and greater production costs of 3D printing. METHODS: To secure sufficient nasopharyngeal swab availability for our national healthcare system, we designed a novel injection molded nasopharyngeal swab (the IM2 swab). We performed a clinical diagnostic study comparing the IM2 swab to the Copan FLOQSwab. Forty patients with a known diagnosis of COVID-19 and 10 healthy controls were recruited. Paired nasopharyngeal swabs were obtained from the same nostril of each participant and tested for SARS-CoV-2 by RT-PCR. RESULTS: When compared to the Copan FLOQswab, results from the IM2 swab displayed excellent overall agreement and positive percent agreement of 96.0% and 94.9%, respectively. There was no significant difference in mean RT-PCR cycle threshold values for the ORF1ab (28.05 vs. 28.03, p = 0.97) and E-gene (29.72 vs. 29.37, p = 0.64) targets, respectively. We did not observe any significant adverse events and there was no significant difference in patient-reported pain. CONCLUSION: In summary, the IM2 nasopharyngeal swab is a clinically safe, highly accurate option to commercial nasopharyngeal swabs.

Design and Multicenter Clinical Validation of a 3-Dimensionally Printed Nasopharyngeal Swab for SARS-CoV-2 Testing.

Importance: Three-dimensionally printed nasopharyngeal swabs (3DP swabs) have been used to mitigate swab shortages during the coronavirus disease 2019 (COVID-19) pandemic. Clinical validation for diagnostic accuracy and consistency, as well as patient acceptability, is crucial to evaluate the swab's performance. Objective: To determine the accuracy and acceptability of the 3DP swab for identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Design, Setting, and Participants: A diagnostic study was conducted from May to July 2020 at 2 tertiary care centers in Singapore with different reference swabs (FLOQSwab [COPAN Diagnostics] or Dacron swab [Deltalab]) and swab processing techniques (wet or dry) to evaluate the performance of the 3DP swab compared with traditional, standard-of-care nasopharyngeal swabs used in health care institutions. The participants were patients with COVID-19 in the first 2 weeks of illness and controls with acute respiratory illness with negative test results for SARS-CoV-2. Paired nasopharyngeal swabs were obtained from the same nostril and tested for SARS-CoV-2 by reverse-transcriptase polymerase chain reaction. The sequence of swabs was randomized based on odd and even participant numbers. Main Outcomes and Measures: Primary outcome measures were overall agreement (OA), positive percentage agreement (PPA), and negative percentage agreement of the 3DP swab compared with reference swabs. Secondary outcome measures were the correlation of cycle threshold (Ct) values of both swabs. Results: The mean (SD) age of participants was 45.4 (13.1) years, and most participants were men (87 of 89 [97.8%]), in keeping with the epidemiology of the COVID-19 pandemic in Singapore. A total of 79 patients with COVID-19 and 10 controls were recruited. Among the patients with COVID-19, the overall agreement and PPA of the 3DP swab was 91.1% and 93.5%, respectively, compared with reference swabs. The PPA was 100% for patients with COVID-19 who were tested within the first week of illness. All controls tested negative. The reverse-transcriptase polymerase chain reaction Ct values for the ORF1ab and E-gene targets showed a strong correlation (intraclass correlations coefficient, 0.869-0.920) between the 3DP and reference swab on independent testing at each institution despite differences in sample processing. Discordant results for both gene targets were observed only at high Ct values. Conclusions and Relevance: In this diagnostic study of 79 patients with COVID-19 and 10 controls, the 3DP swab performed accurately and consistently across health care institutions and could help mitigate strained resources in the escalating COVID-19 pandemic.

Electrostatic expansion of polyelectrolyte microgels: Effect of solvent quality and added salt.

We report dynamic light scattering data for a PNIPAM based microgel copolymerised with 2% ionic groups. The hydrodynamic radius is measured as a function of temperature (which varies the solvent quality) and added salt concentration (cS) from salt-free conditions up to cS = 0.1 M. Incorporation of the ionic co-monomer leads to an increase of the volume phase transition temperature with respect to a non-ionic microgel from T≃306 K to T≃317 K in salt-free water. The hydrodynamic radius varies as RH∝cS-0.05 in good solvent (T≃278-298 K) and RH∝cS-0.15 in poor solvent (T≃313-319 K). Deep into the poor solvent regime the microgel is collapsed for all salt concentrations and RH∝cS0. Data are fitted to the Flory-Rehner model modified to account for the osmotic pressure of the counterions through the Donnan model. We find that the Flory-Rehner-Donnan (FRD) model does not fully account for the experimental observations, particularly at low ionic strengths, possibly due to the influence of electrostatic excluded volume. The disagreements between theory and experiments are greatly reduced if a cross-linking density three times lower than that expected from synthesis is assumed. The scaling theory exponents for the variation of gel size with temperature and added salt are not in agreement with the experimental results presented.

Specific ion versus electrostatic effects on the construction of polyelectrolyte multilayers.

Self-assembled multilayers of a strong polyanion, poly(sodium 4-styrenesulfonate) (PSS), and a strong polycation, poly[(diallyl-dimethyl-ammonium chloride)-stat-(N-methyl-N-vinyl acetamide)] (P(DADMAC-stat-NMVA)), are fabricated on silicon substrates. This article addresses the effect of electrostatics versus ion specificity. Therefore, multilayer formation and growth are investigated as a function of the charge density of the polycation, the type of salt in the polyelectrolyte dipping solution, and its ionic strength. This study focuses on monovalent ions (Li(+), Na(+), K(+), Cs(+), Rb(+), F(-), Cl(-), Br(-), and ClO(3)(-)). Ellipsometry and X-ray reflectometry data indicate that anions have a significantly larger effect on the thickness of the multilayer, but contrary to other studies on ion-specific effects, the influence of the type of cation is not negligible at higher salt concentrations. Larger ions, with smaller hydration shells, are highly polarizable and consequently interact strongly with charged polyelectrolytes, resulting in thicker and rougher multilayers. AFM studies confirm a higher roughness of the multilayer prepared from larger anions. The substrate can mask ion-specific effects over a distance of about 10 nm. Ion-specific effects become important above an ionic strength of 0.1 M in the case of anions and above an ionic strength of 0.25 M for cations. At lower ionic strengths, electrostatic interactions between and within the polyelectrolyte chains are dominating. Reducing the degree of polymer charge down to 75% does not shift this threshold of ionic strength. It is shown that a combination of ionic strength, polymer charge, and type of ion is a suitable tool for tuning the mobility and stability of polyelectrolyte multilayers.

Magnetic nanoparticle-polyelectrolyte interaction: a layered approach for biomedical applications.

This study describes the surface modification of magnetic nanoparticles using two different approaches. The first approach consists of an in situ modification of the surface during the precipitation of the magnetic nanoparticles while the second approach consists of a post-modification of the surface after the formation of the magnetic nanoparticles. In the latter case, we adopted the Layer-by-Layer assembly of polyelectrolyte multilayers of poly(diallyl-dimethylammonium) chloride and poly(styrenesulfonate) to build a polymeric shell around the magnetic nanoparticle core, thereby intentionally conferring to this hybrid core-shell the same charge as the charge of the polyelectrolyte deposited in the last layer. Electrophoretic measurements reveal charge reversal indicating successful Layer-by-Layer deposition while magnetization studies show that the superparamagnetic behavior is not much affected by the presence of polyelectrolytes on the modified magnetic nanoparticles. Fourier transform infrared and thermogravimetry analysis results underline that the various polyelectrolytes employed, in both the methodologies adopted, were successfully bound to the nanoparticles.

Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer.

Histologic grading of breast cancer defines morphologic subtypes informative of metastatic potential, although not without considerable interobserver disagreement and clinical heterogeneity particularly among the moderately differentiated grade 2 (G2) tumors. We posited that a gene expression signature capable of discerning tumors of grade 1 (G1) and grade 3 (G3) histology might provide a more objective measure of grade with prognostic benefit for patients with G2 disease. To this end, we studied the expression profiles of 347 primary invasive breast tumors analyzed on Affymetrix microarrays. Using class prediction algorithms, we identified 264 robust grade-associated markers, six of which could accurately classify G1 and G3 tumors, and separate G2 tumors into two highly discriminant classes (termed G2a and G2b genetic grades) with patient survival outcomes highly similar to those with G1 and G3 histology, respectively. Statistical analysis of conventional clinical variables further distinguished G2a and G2b subtypes from each other, but also from histologic G1 and G3 tumors. In multivariate analyses, genetic grade was consistently found to be an independent prognostic indicator of disease recurrence comparable with that of lymph node status and tumor size. When incorporated into the Nottingham prognostic index, genetic grade enhanced detection of patients with less harmful tumors, likely to benefit little from adjuvant therapy. Our findings show that a genetic grade signature can improve prognosis and therapeutic planning for breast cancer patients, and support the view that low- and high-grade disease, as defined genetically, reflect independent pathobiological entities rather than a continuum of cancer progression.

Direct evidence of layer-by-layer assembly of polyelectrolyte multilayers on soft and porous temperature-sensitive PNiPAM microgel using fluorescence correlation spectroscopy.

We describe the layer-by-layer assembly of polyelectrolyte multilayers on soft and porous temperature-sensitive poly(N-isopropylacrylamide) (PNiPAM) microgel. Microgels are not hard and rigid but rather are soft and porous particles, and polyelectrolytes not only interdigitate with each other during multilayer formation but also with the microgel. Because of this difference, there could be concerns about the feasibility of the layer-by-layer technique on these systems. The argument is that the layer being deposited is stripping the underlying layer instead of anchoring to the latter, and common methods of characterizing film growth on particles such as zeta-potentials will still show "successful" charge reversal. To address this issue, we used two differently labeled polyelectrolytes during the deposition. Because of the small size of the microgel (400 nm) studied, we cannot distinguish between polyelectrolytes adsorbed on or in the microgel. However, with fluorescence correlation spectroscopy, we can clearly distinguish between free labeled polyelectrolytes and those that are bound to the microgel. Dual-color correlation confirms the presence of both polyelectrolytes bound to the same particle while fluorescence imaging (on a dry sample) provides the visual proof.

Global implementation of genomic medicine: We are not alone.

Around the world, innovative genomic-medicine programs capitalize on singular capabilities arising from local health care systems, cultural or political milieus, and unusual selected risk alleles or disease burdens. Such individual efforts might benefit from the sharing of approaches and lessons learned in other locales. The U.S. National Human Genome Research Institute and the National Academy of Medicine recently brought together 25 of these groups to compare projects, to examine the current state of implementation and desired near-term capabilities, and to identify opportunities for collaboration that promote the responsible practice of genomic medicine. Efforts to coalesce these groups around concrete but compelling signature projects should accelerate the responsible implementation of genomic medicine in efforts to improve clinical care worldwide.

Are patients with cancer receiving adequate treatment for thrombosis? Results from FRONTLINE.

The current practice of clinicians worldwide in the treatment of venous thromboembolism was assessed via responses to the FRONTLINE survey. Significant regional differences in practice were noted. Use of low-molecular-weight heparin was reported as the most common initial treatment for venous thromboembolism, although, in North America, unfractionated heparin was widely used to treat surgical cancer patients after a thrombotic episode. Oral anticoagulants were favoured for long-term treatment of venous thromboembolism, particularly in Western Europe and North America. Case study reports from the survey revealed that a substantial proportion of patients with cancer had been perceived to be at low risk of thrombosis, had consequently not received thromboprophylaxis and developed VTE.